PROJECT SUMMARY Despite advances in the treatment of many hematologic malignancies, patients with peripheral T-cell lymphomas (PTCLs) continue to have poor outcomes. Except for the small minority with ALK rearrangements, over 75% of PTCLs fail to respond or rapidly relapse after first-line therapy. FDA-approved drugs for relapsed/refractory PTCL have response rates <30% and median progression-free survival <4 months. Thus, there is an urgent unmet medical need for better therapeutics to treat patients with PTCL. Our central focus is the rational translation of molecular discoveries into informed therapeutic strategies for PTCL. This approach has been very successful for B-cell lymphomas but the low incidence of each PTCL subtype and lack of faithful model systems for in vitro and in vivo studies have prevented similar success for PTCLs. Through concerted effort to overcome these roadblocks, the last 3 years has seen remarkable advances in the understanding and modeling of PTCLs. Our P01 program represents a group of talented, productive and experienced investigators who will attack this daunting clinical problem. The central scientific theme that characterizes all four projects is rapid identification of combination strategies that target PTCL-specific vulnerabilities with non-overlapping mechanisms of resistance, including targeted small molecules and cellular therapies. These strategies will be defined and validated in preclinical models to inform biomarker-driven clinical trials in patients with PTCL. A cornerstone of this P01 program is the shared willingness to make data and resources available open-source. We will address four central, hypothesis-driven Aims. In Aim 1, we hypothesize that targeting of CD25 will overcome buffering of hyperactive T-cell receptor signaling within PTCL cells. In Aim 2, we hypothesize that closely-related but phenotypically-distinct ?? T-cell lymphomas have unique cells-of-origin that confer targetable vulnerabilities. In Aim 3, we hypothesize that agents capable of directly inducing apoptosis can increase therapeutic index in combination with small molecules and CAR T cells directed against PTCL. Many of the proposed studies would not be possible through a single-laboratory funding mechanism, as they rely on cross-disciplinary expertise (e.g. basic T-cell immunology and PTCL therapeutics) and resources (e.g. genomics, noninvasive CAR T cell imaging and in situ assessment of signaling within the PTCL microenvironment) available from the Projects and Cores. The collaborative efforts are supported by an Administrative Core that oversees the budget, communication across the P01 and with the Scientific Advisory Board, fiscal oversight, interactions with the NIH, compliance with institutional and government regulations, biostatistical design and analysis, and general scientific direction. Through this carefully-designed P01 program, we will define a new generation of therapeutic strategies, using combinations with non-overlapping resistance mechanisms, to markedly improve outcomes for patients with PTCL.